Propofol is a widely used general anaesthetic with muscle relaxant properties. Similarly as propofol， the new general anaesthetic AZD3043 targets the GABAA receptor for its anaesthetic effects， but the interaction with nicotinic acetylcholine receptors (nAChRs) has not been investigated. Notably， there is a gap of knowledge about the interaction between propofol and the nAChRs found in the adult neuromuscular junction. The objective was to evaluate whether propofol or AZD3043 interact with the α1β1δε， α3β2， or α7 nAChR subtypes that can be found in the neuromuscular junction and if there are any differences in affinity for those subtypes between propofol and AZD3043. Human nAChR subtypes α1β1δε， α3β2， and α7 were expressed into Xenopus oocytes and studied with an automated voltage-clamp. Propofol and AZD3043 inhibited ACh-induced currents in all of the nAChRs studied with inhibitory concentrations higher than those needed for general anaesthesia. AZD3043 was a more potent inhibitor at the adult muscle nAChR subtype compared to propofol. Propofol and AZD3043 inhibit nAChR subtypes that can be found in the adult NMJ in concentrations higher than needed for general anaesthesia. This finding needs to be evaluated in an in vitro nerve-muscle preparation and suggests one possible explanation for the muscle relaxant effect of propofol seen during higher doses.

BACKGROUND： AZD3043 is a positive allosteric modulator of the γ-aminobutyric acid type A receptor， with sedative and anesthetic properties. We describe a population pharmacokinetic (PK) model of ar ...

The insulin-like growth factor 1 (IGF-1)-AKT-mTOR pathways sense the availability of nutrients and mitogens and respond by signaling for cell growth and division. The p53 pathway senses a variety of stress signals which will reduce the fidelity of cell growth and division， and responds by initiating cell cycle arrest， senescence， or apoptosis. This study explores four p53-regulated gene products， the β1 and β2 subunits of the AMPK， which are shown for the first time to be regulated by the p53 protein， TSC2， PTEN， and IGF-BP3， each of which negatively regulates the IGF-1-AKT-mTOR pathways after stress. These gene products are shown to be expressed under p53 control in a cell type and tissue-specific fashion with the TSC2 and PTEN proteins being coordinately regulated in those tissues that use insulin-dependent energy metabolism (skeletal muscle， heart， white fat， liver， and kidney). In addition， these genes are regulated by p53 in a stress signal–specific fashion. The mTOR pathway also communicates with the p53 pathway. After glucose starvation of mouse embryo fibroblasts， AMPK phosphorylates the p53 protein but does not activate any of the p53 responses. Upon glucose starvation of E1A-transformed mouse embryo fibroblasts， a p53-mediated apoptosis ensues. Thus， there is a great deal of communication between the p53 pathway and the IGF-1-AKT and mTOR pathways. [Cancer Res 2007;67(7)：3043–53]

AZD3043 is a positive allosteric modulator of the γ-aminobutyric acid type A receptor that is rapidly metabolized to an inactive metabolite by esterases present in blood and liver. Preclinical results suggest that AZD3043 has the potential as a short-acting IV sedative/anesthetic drug with rapid and predictable recovery characteristics and a favorable safety and tolerability profile.Our primary objective in this phase 1， single-center， open-label study was to evaluate the safety and tolerability of AZD3043 after IV infusion and to estimate the maximal tolerated dose. Secondary objectives included the evaluation of AZD3043 pharmacokinetics， pharmacodynamics， and efficacy. Sequential ascending-dose cohorts of 5 or 6 healthy male volunteers aged 18 to 45 years received a single 30-minute IV infusion of AZD3043. Assessments included adverse events， vital signs， blood gases， laboratory values， clinical signs of sedation/anesthesia， and bispectral index.Fifty-three subjects received AZD3043 in infusion rate cohorts of 1， 3， 6， 12， 18， 27， 36， 54， and 81 mg/kg/h. There were no discontinuations， and dose escalation was stopped on reaching the predefined exposure limit. Adverse events occurring in >1 subject were headache (n = 4)， erythema (n = 3)， chest discomfort (n = 2)， nausea (n = 2)， and dyspnea (n = 2). The frequency and character of adverse events appeared unrelated to dose. There were no spontaneous reports of pain on injection and no clinically relevant changes in respiratory rate or arterial blood pressure. However， heart rate increased dose-dependently at infusion rates >18 mg/kg/h. Occurrence of sedation/anesthesia corresponded with dose; the lowest applied infusion rate to induce anesthesia according to clinical signs of sedation/anesthesia at predefined time points was 12 mg/kg/h (1 of 6 subjects anesthetized)， and all subjects in the 3 highest dose groups were anesthetized. The onset of anesthesia ranged from 4 minutes in the highest infusion rate group to 29 minutes in the 12-mg/kg/h infusion rate group. Return of response to oral command occurred at 3 minutes after the end of infusion in the single subject who was anesthetized in the 12-mg/kg/h group and median 25 minutes in the 81-mg/kg/h group. Involuntary movements ranging from minor twitches to extensive movements were accompanied by increased muscle tone.AZD3043 was well tolerated in this first human study and seems to exhibit rapid onset and recovery， indicating potential use as a short-acting drug for anesthesia and sedation.

We analyzed 14 cases of new lesions inside implanted bare-metal stents. In every case， there was no angiographic restenosis within 3 years， but a new lesion was observed inside a stented segment at long-term follow-up (>5 years). Fourteen cases were evaluated： 9 with Wiktor stents， 2 with Palmaz-Schatz stents and 3 with ACS Multilink stents. The interval from stent implantation to follow-up angiography was 63–147 months (89±23). Thirteen lesions were treated by percutaneous coronary intervention (PCI) and stenotic tissue was obtained by directional coronary atherectomy (DCA) in 10 cases. All retrieved samples were composed of newly developed atherosclerosis facing the healed neointimal layer， and 4 samples showed histopathological findings of acute coronary syndrome. Stent struts were retrieved in 4 cases and no inflammation was observed surrounding them. Qualitative and quantitative analysis of stent struts was performed in 2 cases that showed no metal corrosion. These findings suggest t